Novel biomaterials their preparation and use

ABSTRACT

The present invention relates to novel materials, particularly biomaterials, in form of a precipitate, comprising at least an anonic polymeric component which is as such soluble in water and an amphiphilic ammonium-type component, which precipitate is obtainable by a process including the following steps: contacting the anionic polymeric component and an cylcodextrin component in an aqueous medium, and adding to the mixture obtained in step 1 said amphiphilic ammonium-type component, wherein said component are present in amounts effective to form said precipitate, and preferably to corresponding precipitates additionally comprising said cycxlodextrin component. Both types of precipitates may optionally comprise one or more further components. The precipitates are particularly useful as controlled-release depot formulations suitable for long-lasting delivery of said further components. The further components incorporated into the precipitates can be pharmaceutical compounds, pesticides, agrochemicals, colorants, diagnostics, enzymes, foodstuffs etc.

The present invention relates to novel polymer-materials, in particular,to novel biomaterials, in form of a specific precipitate, into whichother components may be incorporated, in particular pharmaceuticallyactive agents, which can thereafter be released to their environment ina controlled manner; furthermore the instant Invention relates toprocesses for the manufacture of such precipitates and to pharmaceuticalcompositions and medical devices based on said.

The term “biomaterials” refers generally to materials which have certaincharacteristics related to their behavior in a bio-environment. Inparticular, such materials must disintegrate in a natural environmentand should metabolize after fulfilling their purpose without leaving anytrace. Furthermore, biomaterials should not invoke an adverse response,for instance an inflammatory or toxic response in the environment inwhich they are used. In addition to that, they should be easy tosterilize and easy to process into a desired product form. It is also ofgreat advantage if such materials exhibit mechanical properties thatsuit to the intended application and if they attend an acceptable shelflife.

The first polymeric biomaterials prepared from glycolic acid and lacticacid have found a multitude of uses in the biomedical industry,beginning with the biodegradable sutures first approved in the 1960s.Since that time, diverse products based on lactic and glycolic acid—andon other materials, including poly(dioxanone), poly(trimethylenecarbonate) copolymers, and poly(ε-caprolactone) homopolymers andcopolymers—have been accepted for clinical uses as medical devices. Inaddition to these approved devices, a great deal of research continueson polyanhydrides, polyorthoesters, polyphosphazenes, and otherbiodegradable polymers.

Polymeric biomaterial can be either natural or synthetic. In general,synthetic polymer-materials offer certain advantages over naturalmaterials, particularly because they can be tailored to give a widerrange of properties and a more predictable lot-to-lot uniformity thanmaterials from natural sources. Synthetic polymers also represent a morereliable source of raw materials, and one free from concerns ofimmunogenicity. Novel synthetic polymer-materials having the importantcharacteristics of biomaterials are therefore still stronglysought-after.

It is an objective of the instant invention to provide such novel solidmaterials, in particular biomaterials having all of the characteristicsmentioned above. These materials shall be able to incorporate furthercomponents, including particularly pharmaceutically active agents,inside of their matrix, and to release said components thereafter in acontrolled and reproducible manner, particularly in a prolonged manneras compared to when said further components would have been administeredin usual form.

It has now surprisingly been found that novel compositions comprising atleast an anionic polymeric component which is as such soluble in waterand an amphiphilic ammonium-type component, and which may furthermorecomprise a cyclodextrin component, meet the objective mentioned above.These compositions are specific precipitates comprising the first two orall three aforementioned components, and can be characterized in thatthey are obtainable by a process which includes the following processsteps:

-   -   1. contacting the anionic polymeric component and the respective        cyclodextrin component in an aqueous medium, and    -   2. adding to the mixture obtained in step 1 the amphiphilic        ammonium-type component.

Certain compositions, in particular pharmaceutical compositions, whichcomprise, in addition to a pharmaceutically active agent, a cyclodextrincompound and a quaternary onium compound as preservative, inclusive ofpreservatively effective amphiphilic onium compounds like for instancebenzalkonium chloride, benzoxonlum chloride, cetylpyridinium chloride orcetyltrimethylammonium bromide, and furthermore a carrier whichoptionally may also comprise a polymer, inclusive of water-solubleanionic polymers, for instance carboxymethyl cellulose, starchderivatives, alginates, pectins, xanthan gum, tragacantha gum orpolyacrylic-add-type polymeric components, are already known in the art,and are disclosed In EP-A-0 862 414.

Except from the fact, however, that these compositions comprise thequarternary onium compound only in amounts necessary to provide apreservative effectiveness, in particular in amounts of 0.5 percent byweight (% bw) maximum, said compositions have also been designed to meetan objective which is entirely different from that of the instantinvention, inasmuch as these compositions are intended to maintain thebio-availability enhancing effect which cyclodextrin compounds usuallyhave on pharmacologically active agents which are used in combinationtherewith, and to simultaneously enhance the preservative efficacy of apreservative which is lower than usual in the presence of a cyclodextrincompound. In order to achieve this objective, it is obligatory thatthese compositions comprise an alkylene glycol compound as a furthercomponent which provides the above mentioned functionality, in additionto its usual functionality as a tonicity and/or solubility enhancingagent. The presence of such alkylene glycol compounds is by no meansessential for the instant invention.

Furthermore, the compositions specifically disclosed in EP-A-0 862 414are either aqueous solutions or, in one case, a strongly watery gelhaving about 95% bw of water content, and even though the referencementions that the disclosed compositions could also have the form of asolid insert, it does not disclose any specific form of a suitable solidmaterial for use as such insert, particularly not a precipitate obtainedby contacting the anionic polymeric and the cyclodextrin component in anaqueous medium, and adding thereto the amphiphilic ammonium-typecomponent, if desired in the presence of further components.

A first subject of the instant invention is accordingly a precipitatecomprising at least an anionic polymeric component which is as suchsoluble in water and an amphiphilic ammonium-type component, whichprecipitate is obtainable by a process which includes the followingprocess steps:

-   -   1. contacting the anionic polymeric component and a cyclodextrin        component in an aqueous medium, and    -   2. adding to the mixture obtained in step 1 the amphiphilic        ammonium-type component;        wherein said components are present in amounts effective to form        said precipitate.

The obtained precipitates usually comprise all three componentsmentioned above, that is to say the anionic polymeric component, theamphiphilic ammonium-type component and the cyclodextrin component. Incertain cases, however, it has been found that substantially nocyclodextrin component is incorporated into the precipitate,notwithstanding the fact that the process is carried out as describedabove.

This can readily be detected, for example by use of HPLC analysis of theobtained precipitates and has particularly no influence on the abilityof said substance systems to incorporate further compounds inside oftheir matrix and to release them again in reproducible and controlledmanner as described above.

Examples of such cyclodextrin-free precipitates are the precipitatesobtainable by applying the above described process on poly(meth)acrylicacid type polymers and hyaluronic acid together with certain amphiphilicammonium-type compounds, e.g. cetyldimethyl(2-hydroxyethyl)ammoniumdihydrogen phosphate, benzalkonium chloride or palmitoyl carnitine andgamma-cyclodextrins.

A first particularly useful specific embodiment of the materialsaccording to the invention is a precipitate comprising said anionicpolymeric component and said amphiphilic ammonium-type component and oneor more further components, for instance components selected frompharmaceutically active agents, pesticides, agrochemicals, colorants,diagnostics, enzymes, foodstuffs and so on, which precipitate ischaracterized in that it is obtainable by carrying out the process stepsmentioned above in the presence of said one or more further components,which are, for instance, added in course of step 1 and/or 2.

A second particularly useful specific embodiment of the materialsaccording to the invention is a precipitate comprising said anionicpolymeric component, said amphiphilic ammonium-type component, acyclodextrin component, and one or more further components, for instancecomponents selected from pharmaceutically active agents, pesticides,agrochemicals, colorants, diagnostics, enzymes, foodstuffs and so on,which precipitate is characterized in that it is obtainable by carryingout the process steps mentioned above in the presence of said one ormore further components, which are, for instance, added in course ofstep 1 and/or 2.

The precipitates according to the invention are, particularlyadvantageous, obtainable by dissolving the anionic polymeric component,the cyclodextrin component and, if present, further components comprisedin said precipitate which are as such soluble in water, in an aqueousmedium as carrier to form a first composition; dissolving theamphiphilic component and blending therewith in a suitable liquidcarrier, preferably also an aqueous medium, if present, furthercomponents comprised in said precipitate which are insoluble in water,to form a second composition, and contacting said first and secondcomposition to form the corresponding precipitate according to theinvention, separating itself from the mother liquor.

The anionic polymeric component, the amphiphilic component and thecyclodextrin must be present in amounts which are effective to form aprecipitate. These amounts may vary to a great extent, depending, forinstance, on the specific compounds used for manufacturing a certainprecipitate, the specific composition of the aqueous carriers as well asthe processing parameters. Preferably, however, the anionic polymericcomponent is used in a quantity of 5 to 30% bw, in particular 7 to 25%bw, based on the total quantity of anionic polymeric component,amphiphilic component and cyclodextrin component, whereas theamphiphilic component and cyclodextrin component are preferably used ingreater amounts, for instance the cycoldextrin component in quantitiespreferably ranging from 20 to 70% bw, in particular 35 to 65% bw, basedon the total quantity of anionic polymeric component, amphiphiliccomponent and cyclodextrin component. The amphiphilic component ispreferably used in quantities of 10 to 75% bw, more particularly of 15to 70% bw, most particularly of 25 to 60 % bw, based on the totalquantity of anionic polymeric component, amphiphilic component andcyclodextrin component. This is more than about hundred times of what isnecessary when such amphiphilic ammonium-type compounds are used tofunction as preservative as disclosed in EP-A-0 862 414 (cf. forinstance Example 2 of this reference, the description of which isexplicity included into the instant application).

Suitable concentrations of the anionic polymeric component, theamphiphilic component and the cyclodextrin in the aqueous medium or thecarrier into which they are incorporated for being contacted with oneanother depend, of course, on the solubility of these components in saidmedium or said carrier. On the other side, due to the low solubility ofthe precipitates according to the instant invention in aqueous media,these concentrations are rather uncritical and may be rather low,ranging for instance from about 0.1% bw or even lower values upward. Themaximum concentration, on the other side, is generally limited only bythe limited solubility of the components in question in the aqueousmedium or the carrier. Concentrations, which are particularlyadvantageous in practice, range, for instance, from 0.5% bw to 50% bw(where possible), preferably from 0.5% bw to 35% bw, especially 1% bw to20% bw.

For the purposes of the instant application “aqueous medium” and“aqueous carrier” are to be understood as a liquid medium or carriercomprising water as one, in particular as the major liquid component,preferably being present in amounts of 90 to 100% bw of the entireaqueous medium or carrier. The presence of non-aqueous liquids in theaqueous medium or carrier is not critical, as long as it does notprevent the formation of the precipitate, that means as far as theprecipitate is still sufficiently insoluble in the aqueous medium to beformed. The non-aqueous liquids must, of course, be acceptable in viewof the intended use of the precipitate. In a more preferred sense“aqueous medium” and “aqueous carrier” shall mean a liquid medium orcarrier comprising water and 0 to not more than 5% bw of one or morenon-toxic non-aqueous liquids as the liquid components. Most preferably,water of a suitable grade depending on the requirements of theapplication, for instance, a de-ionized and/or sterilized water, is theonly liquid component which present in the aqueous medium or carrier.

The precipitates according to the instant invention are highly insolublein aqueous media, as already mentioned above. Once the anionic polymericcomponent, the amphiphilic component, the cyclodextrin and thecomponents, if present, have been brought into contact in the aqueousmedium, the precipitates form generally rather fast, for instance incourse of a time period of a second or less to about 30 minutes. Theyield in precipitate which can be isolated is normally in a range of 30to 100% bw of the theoretically possible value (that is the sum of thequantities of said educts), for instance 40 to 90% bw. The precipitatesmay of course comprise a certain amount of the liquid components oftheir mother liquor, that means In particular of water, the amount ofwater ranging, for instance, from about 2 to 50% bw based on the entireprecipitate. Wet forms as obtained right after reaction contain usuallyhigher amounts of water, for instance about 40% bw. Depending on thespecific after-treatment of the precipitate (drying parameters etc.) thewater content decreases in general to values ranging frequently from 2to 30% bw, for example from 10 to 20% bw. It is so possible to prepareprecipitates according to the instant invention having an even lowercontent in water.

Although the detailed internal structure of the precipitates accordingto the invention Is not yet known, and without wanting to be bound toany theory, it is Indicated by HPLC analysis of the precipitates thatthe components comprised in therein, in particular the anionic polymer,the amphiphilic compound and the cyclodextrin compound, do not reactwith one another in a chemical sense when forming said precipitate, inparticular, it does not seem as if covalent bonds would exist betweenany of these compounds.

The precipitates according to the invention generally fulfill thecriteria expected from useful biomaterials. In particular, theprecipitates do not invoke an inflammatory or toxic response. They canbe easily processed into a desired product form, can easily besterilized, and exhibit an acceptable shelf life. Furthermore, theyexhibit good mechanical properties. So, for instance, if the material isused for supporting injured tissue, its mechanical strength remains, ingeneral, sufficiently strong until the surrounding tissue has healed.

Certain materials according to the Invention show electric conductivity,for instance a material comprising a precipitate comprising hyaluronicacid as the anionic polymer component, gamma-cyclodextrin,cetyl-dimethyl-(2-hydroxyethyl)-ammonium dihydrogenphosphate as theamphiphilic compound and optionally elemental iodine.

Moreover, the precipitates according to the invention disintegrate fastin a natural environment and finally metabolize, for instance, in thebody after having fulfilled their purpose without leaving traces. Thisbiodegradation is, in general, the faster the more hydrophilic thebackbone of the anionic polymeric component is, the more hydrophilicend-groups it has and the more hydrolytically reactive groups itsbackbone has, as well as the poorer the crystallinity and the strongerthe porosity of the polymeric material is, which is comprised in theprecipitates according to the invention.

A particularly surprising and valuable aspect of the instant inventionis, that the precipitates according to the instant invention provide awater-insoluble matrix vehicle which can incorporate other componentsinside of this matrix. Without wanting to be bound to any theory, itappears that these additional components are partially carried inmolecularly-entrapped form in the cyclodextrin groups of the precipitateand/or partially bound by other physical forces in themicellar-polymeric structure of the precipitate. Said other componentsare released by the precipitate In a reproducible and controllablemanner, particularly in a prolonged manner as compared to when saidfurther components would have been administered in free form, so thatprecipitates according to the invention which comprise such furthercomponents incorporated into themselves represent depot formulations ofthese further compounds.

A preferred embodiment of the precipitates according to the inventiontherefore comprises one or more further components, in addition to thosementioned above as already mentioned above. These other components are,for instance, selected from pharmaceutically active agents, pesticides,agrochemicals, colorants, diagnostics, enzymes and foodstuffs.

The anionic polymeric component of the precipitates according to theinstant invention comprises one or more than one anionic water solublepolymers in admixture.

With regard to these polymers “water soluble” means for the purposes ofthis application that at least 0.5% bw and more, in particular 1% bw andmore of the polymer component can be dissolved in water. Suitableconcentrations depend, in general, on the viscosity of the resultingsolution. Frequently it is difficult to handle aqueous solutions of morethan 2 to 3% bw of the polymer component because such solutions havealready a too high viscosity. Sometimes such solutions may already be“solid” hydrogels.

The term “anionic polymer” means for the purposes of the instantapplication a polymer comprising groups, which are at least partiallydissociated in an aqueous medium, thereby forming anionic moleculargroups bound to the polymer and imparting water solubility to thepolymer compound, for example carboxylic acid or carboxylic acid saltgroups. Suitable anionic polymers include non-toxic water-solublepolymers, such as hyaluronic acid, carboxymethyl-cellulose, othercellulose derivatives, such as methylcellulose, carboxy-methylcellulose,hydroxymethylcellulose, hydroxyethylcellulose,methylhydroxypropyl-cellulose and hydroxypropylcellulose,poly(meth)acrylic acid type polymers, like polyacrylic acids, such asneutral Carbopol®, or ethyl acrylate, polyacrylamides, natural products,such as gelatin, alginates, pectins, tragacanth, karaya gum, xanthangum, carrageenin, agar and acacia, starch derivatives, such as starchacetate and hydroxypropyl starch carboxymethyl starch and water-solublesalts of such polymers, and also other synthetic products, such aspolyvinyl alcohol, polyvinyl pyrrolidone, polyvinyl methyl ether orpolyethylene oxide.

Preferred anionic polymers are hyaluronic acid, carboxymethyl cellulose,carboxymethyl starch, alginic acid, polyacrylic-acid-type polymericcomponents, pectin, xanthan gum, tragacantha gum, water-soluble salts ofone of said components and mixtures of two or more of said polymers orpolymer salts. Particularly preferred are hyaluronic acid, carboxymethylcellulose xantan gum, water-soluble salts of one of said components andmixtures of two or more thereof.

The amphiphilic ammonium-type component of the precipitates comprisesone or more amphiphilic ammonium-type compounds. Suitable amphiphilicammonium-type compounds include monomeric compounds having one or more,for instance two, quaternized ammonium groups and polymeric compounds,for instance polymers or copolymers of monomers having a quaternizedammonium group. The molecular weight of suitable polymeric ammonium-typecompounds ranges for instance, from 10000 to 1500000, in particular from35000 to 1000000 (determined with the light scatter method), the chargedensity, for instance, from 0.1 to 15, in particular from 0.1 to 10meq/g. For the purposes of this application, the term “ammonium-typecompound” is understood as including also quaternized N-heterocycliccompounds, for instance N-substituted pyridinium compounds.

Suitable amphiphilic onium type compounds include cationic surfactants,several of which are commercially available. Particularly preferredamphiphilic ammonium-type compounds are, for instance,benzalkonium-chloride, benzoxonium-chloride, cetylpyridinium chloride,cetyltrimethylammonium bromide, cocamidopropyl-N,N,N,trimethylglycine,palmitoyl carnitin, sodium-cocylglutamate. Particularly preferred aswell are surfactants as marketed under the trademark Luviquat® (BASF)and similar types. These include monomeric compounds like, for instance,Luviquat®MONO CP, a 30% aqueous solution ofcetyldimethyl(2-hydroxyethyl)ammonium dihydrogen phosphate;Luviquat®MONO LS, a 30% solution of lauryl/myristyl-trimethylammoniummethylsulfate in water (charge density c. 2.9 meq/g; or Luviquat® Dimer18, a 50% solution of hydroxypropylbisstearyidimethylammonium chloridein a 50/50 mixture of water and ethanol. Suitable surfactants alsoinclude polymeric compounds, in particular copolymers ofvinylpyrrolidone and/or vinylcaprolactam with monomers having anquaternized ammonium group like trialkylammonium(meth)acrylates orN-alkylvinylimidazolinium compounds. Suitable polymeric surfactantshave, for instance, a molecular weight between 25000 to 1000000 and more(determined with the light scatter method) and a charge density rangingfrom 0.3 to 10 meq/g. Examples include Luviquat® Q 11 PN, a copolymer of67% bw vinylpyrrolidone and 33% bw dimethylethylammonium-methacrylateethylsulfate having a molecular weight (determined with the lightscatter method) of c. 1000000 and a charge density of 0.8 meq/g, in anaqueous solution of 19-21% solids content; Luviquat®Hold, a copolymer of50% bw vinylcaprolactam, 40% bw vinylpyrrolidone and 10% bwN-methylvinylimidazolinium methylsulfate having a molecular weight(determined with the light scatter method) of c. 700000 and a chargedensity of 0.5 meq/g in a water/ethanol solution of 19-21% solidscontent; as well as Luviquat®FC 370, Luviquat®HM 552, Luviquat®FC 905,Luviquat®Care, which are copolymers of vinylpyrrolidone (VP) andN-methylvinylimidazol (QVI) in aqueous solution having a composition asdetailed in the following table: Composition Charge [% bw] SolidsMolecular Density Trademark VP QVI Anion Content [%] Weight^(A)) [meq/g]Luviquat ® FC 370 70 30 Cr 38-42 c. 100000 2.0 Luviquat ® FC 550 50 50Cr 38-42 c. 80000 3.3 Luviquat ® HM 552 55 45 Cr 19-21 c. 400000 3.0Luviquat ® FC 905 5 95 Cr 38-42 c. 40000 6.1 Luviquat ® Care 80 20H₃CSO₄ ⁻ 6-7 c. 1000000 1.09^(A))determined with the light scatter method

Suitable commercially available surfactants may also comprise smallamounts of additives, for instance preservatives like alkylparabencompounds, and inert organic solvents, and can be readily elected by theskilled person according to the requirements in a specific field of useof the precipitates.

Another specific embodiment of suitable amphiphilic ammonium typecompounds are corresponding cationic phospholipids, in particularlysophosphatidyl-choline compounds, phosphatidyl choline compounds like,for example, egg-yolk-phosphatidyl choline, sphingomyelin, correspondingsphingosine derivatives and mixtures thereof. Phospholipids like thosehave the advantage that they are of natural origin and thereforeespecially compatible to tissue, on the other side it has been foundthat hardness and consistency of precipitates comprising amphiphiliccomponents of this type is less favorable as compared to precipitatesaccording to the invention based on other amphiphilic ammonium-typecompounds. Phospholipids may also be used in combination with otheramphiphilic ammonium-type compounds, in particular in combination withthose amphiphilic ammonium compounds mentioned above.

The amphiphilic ammonium type compounds selected from the groupconsisting of benzalkonium-chloride, benzoxonium-chloride,cetylpyridinium chloride cetyltrimethyl-ammonium bromide,cetylpyridinium chloride cetyltrimethylammonium bromide;cetyldimethyl(2-hydroxyethyl)ammonium dihydrogen phosphate (Luviquat®Mono CP), cocamidopropyl-N,N,N,trimethylglycine, acyl carnitinederivatives, for example those described in U.S. Pat. Nos. 4,194,006 or5,731,360, in particular palmitoyl carnitine; sodium cocyl glutamate andmixtures of one or more members of said group are a particularlypreferred choice for precipitates of the instant invention.

The cyclodextrin component of the precipitates according to the instantinvention may comprise one or more cyclodextrin compounds. Acyclodextrin compound as is referred to within the present applicationis either alpha, beta or gamma-cyclodextrin itself, a derivativethereof, for instance, a partially etherified derivative as e.g. ahydroxyalkyl ether derivative or a mixture thereof. It should be notedthat a randomly chosen cyclodextrin compound does not automatically forman inclusion complex with any randomly chosen other compound, which maydesired to be incorporated into the precipitates of the instantinvention. In such cases it is therefore preferred to use thecyclodextrin compound that meets the cavity needs of other the componentor components to be incorporated into the precipitate. Thesecorrelations are known to those skilled in the art.

Appropriately substituted alpha-, beta- or gamma-clodextrins are, forinstance, alkylated, hydroxyalkylated, carboxyalkylated oralkyloxycarbonyl-alkylated derivatives. Other typical examples arecarbohydrate derivatives of cyclodextrins such as mono- ordiglycosyl-alpha-, -beta- or -gammaclodextrin, mono- ordimaltosyl-alpha-, -beta- or -gamma-cyclodextrin orpanosyl-cyclodextrin.

Preferred precipitates according to the Instant invention includeparticularly those wherein the cyclodextrin component is selected fromalfa-cyclodextrin, beta-cyclodextrin, gamma-cyclodextrin and mixturesthereof.

Where desired, the precipitates according to the invention may alsocomprise small amounts, for instance effective amounts from 0.0001 up to5% bw, e.g. 0.1 to 3% bw, of compatible additives like, for example,stabilizers or preservatives, and compatible modifiers, for instanceplasticizers or flexibilizers, in addition to the components mentioned.

The precipitates according to the invention can, for instance, bemanufactured by a process wherein the anionic polymeric component, theamphiphilic ammonium-type component, the cyclodextrin component andother components to be incorporated into the precipitate are contactedwith one another either consecutively or simultaneously in an aqueousmedium in amounts effective to form said precipitate, wherein at leastthe anionic polymeric component, the amphiphilic component and thecyclodextrin component are present in a dissolved form when contacted,and wherein the amounts of the components are chosen such that theprecipitate forms.

The formation of the precipitate in the above described process causesan immediate decrease of the viscosity of the reaction mixtures. Theprecipitate can thereafter be isolated, for instance by filtration orcentrifugation, as a wet polymer.

Optionally, a dry precipitate can be obtained after sufficient andcareful drying. Drying can, for instance, advantageously be accomplishedby immersing the wet precipitate material, optionally after washing itone or several times, preferably with water, into a cooled volatileorganic solvent, for instance acetone, having a temperature ofpreferably less than 12° C., leaving the material in contact with saidsolvent for a certain time period, for instance a few minutes to aboutone hour, separating it thereafter and removing the remaining solvent,optionally at elevated temperature and/or under vacuum.

The dry precipitate when contacted with water again turns into anelastic, flexible, rubber-like plastic, that does not show significantswelling in water upon re-wetting. The re-wetted matrix appearsphysically stable when stored in water at ambient temperature for atleast 6 months. No bacterial or fungal infections were observed whenre-wetted matrix was stored for 6 months in sealed polyethylene bagscontaining de-ionised water.

If desired, the precipitate can easily be brought into any desired shapeusing conventional methods, like pressing or rolling for instance. Justlike that it is possible to form fibers, sheets, or threads from theprecipitates according to the invention.

In a preferred embodiment of the process for manufacturing the describedprecipitates, the anionic polymeric component, the cyclodextrincomponent and further components which are soluble in water and are tobe incorporated into said precipitate are dissolved in an aqueous mediumto form a first composition; the amphiphilic ammonium-type component andfurther components which are insoluble in water and are to beincorporated into said precipitate, are blended with a suitable liquidcarrier, preferably also an aqueous medium, to form a secondcomposition, and said first and second composition are blended to formsaid precipitate.

This embodiment of the process can, for instance, advantageously be usedto form a coating of a precipitate according to the instant invention ona solid carrier. In this case, the process includes coating the carrierwith said first composition, and a subsequent treatment of theso-treated carrier with said second composition to form a coating ofsaid precipitate thereon. Administration of said first and/or secondcomposition onto the carrier can, for instance, be achieved by spraying,or by any other suitable method.

With regard to their biomaterial-properties, the precipitates accordingto the instant invention are particularly useful for biomedicalapplications. They can be used as such, that means without any furthercomponents, for instance, for making biodegradable surface coatings,surgical wound covers, dressings or threads.

A specifically useful embodiment of the instant invention however, areprecipitates comprising one or more further components which comprise apharmaceutically active agent. The pharmaceutically active agent may,for instance, be selected from the group consisting of steroids,prostanoids, nitric-oxide prodrugs, antihistamines, antibiotics,cytostatic agents, antivirals, peptide hormones, local anesthetics,antiglaucoma agents, antiinflammatory agents, antihypertensives,antiangiogenic agents and suitable mixtures thereof. The amount ofpharmaceutically active component can vary in broad ranges and accordingto the specific indication and requirements. Suitable amounts ofpharmaceutical active ingredient range, for instance from 1 to 20% bw,especially from 3 to 15% bw, more especially from 5 to 10% bw, based onthe entire precipitate.

These pharmaceutically effective precipitates are, among other things,useful for manufacturing medical devices such as medical implants orinserts, or medical surface coatings, surgical wound covers or threads.

Particularly preferred, however, is the use of such precipitates in themanufacture of pharmaceutics. The invention therefore also relates to apharmaceutical composition comprising a precipitate according to theinvention which comprises a pharmaceutically active agent.

In particular, the generally pro-longed release of pharmaceuticallyactive agents from the precipitates as compared to when saidpharmaceutically active agents would be administered in free form, makesthe precipitates of the instant invention extremely useful, forinstance, for manufacturing depot formulations of all types ofpharmaceutically active agents.

While said pharmaceutical compositions can, of course, be administeredin any suitable way, it is also possible to administer such compositionsby consecutive or simultaneous administration of one or morecompositions, each comprising one or more than one of the components ofthe precipitate intended to administer, and forming said precipitate insitu at the place of administration. By the way of example, such partialcompositions can, for instance, be injected into a living body, e.g.subcutaneously or intramuscularly, in order to form thereby in situ asubcutaneous or intramuscular depot of a desired pharmaceutically activeagent at a desired place. It is as well possible, for instance, toadminister pharmaceutical compositions onto wounds, skin or other solidorganic surfaces by consecutively spraying such partial compositionsonto the desired place thereby forming a coating at said place which isable to deliver a desired pharmaceutically active agent at said placeover a long time period.

A further subject of the instant invention is therefore a kit foradministering a pharmaceutical composition according to the instantinvention to a subject by simultaneous or preferably consecutiveadministration of parts of said composition to said subject therebyforming said composition in situ at the place of administration, whichkit comprises two or more than two partial compositions, each comprisingone or more but not all of the components of said pharmaceuticalcomposition, whereby the components intended to form the precipitate arepresent in said compositions for consecutive or simultaneousadministration in amounts effective to form the precipitate whencontacted with one another.

A specific form of the described kit comprises a first compositioncomprising the anionic polymeric component, the cyclodextrin componentand the further components to be incorporated into said precipitatewhich are soluble in water, dissolved in an aqueous medium; and a secondcomposition comprising the amphiphilic ammonium component and thecomponents to be incorporated into said precipitate which are insolublein water, blended with a suitable liquid carrier, preferably an aqueousmedium.

Specific embodiments of this kit include corresponding kits forsubcutaneous or intramuscular administration of the pharmaceuticalcomposition, and for administration of the pharmaceutical composition byspraying, for instance onto wounds, skin or other solid organicsurfaces.

A further subject of the instant invention is a method of administeringa pharmaceutically active compound to a subject in need thereof,comprising the administration of a pharmaceutical composition accordingto claim 15 or 16 comprising said pharmaceutically active compound.

Still another subject of the invention is a method for administering apharmaceutical composition as described above to a subject including thesimultaneous or preferably consecutive administration of two or morethan two partial compositions, each comprising one or more of thecomponents of said pharmaceutical composition, thereby forming thepharmaceutical composition in situ at the place of administration,wherein the components intended to form the precipitate are present insaid partial compositions in amounts effective to form the precipitatewhen contacted with one another.

A specific embodiment of said method includes the simultaneous orpreferably consecutive administration of a first composition comprisingthe anionic polymeric component, the cyclodextrin component and thefurther components comprised in said precipitate which are soluble inwater, dissolved in an aqueous medium; and a second compositioncomprising the amphiphilic component and components comprised in saidprecipitate which are insoluble in water, blended with a suitable liquidcarrier, preferably an aqueous medium.

The partial compositions can, for instance, be subcutaneously orintramuscularly injected in the subject or be administered onto wounds,skin or other solid surfaces of a subject, preferably by spraying.

The following examples explain the invention in more detail.

EXAMPLE 1 Preparation of the HyaluronicAcid/Surfactant/Gamma-Cyclodextrin Biomaterial

This Example describes a basic precipitate according to the inventionand a method for preparing the same.

50 g of gamma-cyclodextrin (gCD) is dissolved in 950 g of deionizedwater at 25° C., resulting in a slightly hazy solution. To the stirredgCD solution 10 g of sodium-hyaluronate is added and the mixture isstirred for 60 minutes at 25° C. to obtain a clear or slightlyopalescent, dense solution with no solid particles. To this aqueoussolution 65 ml of Luviquat Mono CP solution containing 30% (19.5 g) ofcetyl-dimethyl-(2-hydroxy-ethyl)-ammoniumdihydrogen-phosphate is addedduring agitation with 150 r.p.m. (The commercial Luviquat Mono CPsolution is purchased from BASF). The solution turns a white suspensionand in about 20 minutes after addition of the surfactant white,rubber-like polymer precipitate is formed. The reaction mixture isstirred for an additional 10 minutes with 150 r.p.m, then allowed tostand at ambient temperature to settle down the body precipitate. Theproduct is isolated by filtration and washed 3-times with 500 ml ofdeionised water. The washed wet product is a white rubber likeviscoelastic polymer. After drying in vacuum at ambient temperature 60 gof white, amorphous solid is obtained. (yield: 75%)

Three different batches following the above technology were prepared andanalyzed by HPLC method. Table 1. lists the analysis results of theformed insoluble polymeric matrices after redissolved in methanol. TABLE1 HPLC analysis results of the composition of precipitates preparedaccording to Example 1. composition by HPLC (%) Batch No. Na-hyaluronateg-CD Luviquat ® Mono CP yield (%) 20/51/1 12.4 56.9 18.0 75 20/51/2 12.752.0 26.3 74 20/51/3 12.8 52.0 26.0 71

It is concluded from the above data that the reproducibility of themanufacturing method is acceptable. The products prepared according toExample 1. have similar composition as shown by HPLC analysis. Themother liquor of the above reaction mixture was analysed by HPLC andfound to contain both gCD and surfactant, but not even traces of thehyaluronic acid sodium salt.

It is moreover of analytical importance to know the actual water contentof these dried biometrials. The water content of samples was determinedby both loss on drying and Karl-Fisher methods. The water content ofthree consecutive batches is given in Table 2 below: TABLE 2 Watercontent and loss on drying values of the biomaterials according toExample 1. water content by Karl Fisher Sample (%) Loss on drying (%)20/51/1 14.3 15.9 20/51/2 14.8 15.5 20/51/3 14.0 16.0

Differential scanning calorimetry shows water losses of at differenttemperature ranges. This indicates that the water content of samplesaccording to the present invention is composed from water fractionsbound in different manner.

EXAMPLE 2 Physical and Chemical Characterization of the BiomaterialsAccording to Example 1

Chemical Composition

The analysis of the composition of the hyaluronicacid/surfactant/gamma-cyclodextrin biomaterials was carried out by usingHPLC and Capillary Electrophoresis techniques. These techniques besidesthe composition of the matrices gave information about the chemicalintactness of all three components present in the matrix, indicatingthat no chemical conversion of the components took place upon formationof the biomaterial. Near-infrared (NIR) and NMR spectroscopy providedfurther evidence to the fact that no new chemical entity is formed uponthe interaction of the three component yielding water-insoluble matrix.

Solid State Characteristics of Hyaluronic Acid/qCD/Surfactant Matrix

The white, stone hard solid matrix appears X-ray amorphous. No exactmelting point can be determined by using conventional melting pointapparatus. Upon heating the solid material does not show any phasetransition up to 210° C., however, above this temperature the polymermatrix turns brown and gets thermally degraded.

Thermal analysis by Differential Scanning Calorimetry in inert gasatmosphere has further supported the above observation. In nitrogenatmosphere the biomaterials according to the present invention show noexact melting endothermic peak. However, they are characterized by avery broad endothermic heat flow, taking place between 40-188° C. Thisprocess has a maximum at around 100° C., thus it seems to be related tothe loss of bound water. At higher temperatures this process is probablyoverlapped by a glass transition. The endothermic heat-flow is followedfrom 188° C. by a sharp exothermic heat-flow with a maximum at 215° C.This is assumed to be the consequence of either a solid state chemicalreaction between the constituents, or—more likely—the thermaldegradation of the polymeric matrix.

EXAMPLE 3 Preparation of a Luviquat Mono CP Surfactant/HyaluronicAcid/Alfa-Cyclodextrin Biomaterial

16 g of alfa-cyclodextrin (aCD) is dissolved in 150 g of deionised waterat 25° C. To the stirred aCD solution 2.0 g of sodium-hyaluronate isadded and the mixture is stirred for 45 minutes at 25° C. to obtain aclear dense solution. To this solution 6.6 ml of Luviquat Mono CP (a 30%aqueous solution purchased from BASF) is added during agitation. Thesolution turns a white suspension and in 30 minutes after addition ofthe surfactant white rubber-like polymer precipitate occurs. Thereaction mixture is stirred for 30 minutes, then allowed to stand atroom temperature to settle down the precipitate. The precipitate isisolated by filtration and washed with 5 times 30 ml of deionised water.After drying in vacuum at ambient temperature 12 g of a white, glassysolid is obtained. (yield: 60%)

EXAMPLE 4 Preparation of a Luviquat Mono CP Surfactant/HyaluronicAcid/Beta-Cyclodextrin Biomaterial

18 g of beta-cyclodextrin (bCD) is dissolved in 800 grams of deionisedwater at 37° C. To the stirred bCD solution 2.0 g of sodium-hyaluronateis added and the mixture is stirred for 30 minutes at 37° C. to obtain aslightly opalescent dense solution with no solid particles in it. Tothis solution 6.5 ml of Luviquat Mono CP (a 30% aqueous solutionpurchased from BASF) is added during agitation. The reaction mixture iscooled from 37° C. to 25° C. solution turns a white suspension and in 45minutes after completing the addition of the surfactant white, amorphouspolymer precipitate occurs. The reaction mixture is stirred for 30minutes at 20° C., then allowed to stand at refrigerator. Theprecipitate is isolated by filtration and washed with 5 times 15 ml ofdeionised water. After drying in vacuum at ambient temperature 7.0 g ofwhite, glassy solid is obtained. (yield: 31.8%)

Replacement of Hyaluronic Acid With Other Anionic Polymers

It has been found that the basic phenomenon of the formation ofwater-insoluble biomaterials observed for hyaluronicacid/quaternary-ammonium-type surfactant/and cyclodextrins occurs alsowith some other water-soluble, anionic polymers of different chemicalstructure. It is assumed that anionic polymers react with cationicamphiphilic molecules (e.g. surfactants) via an ionic interaction andcyclodextrins are bound to this macromolecular salts by apolar-apolarinteraction on the lipophilic tail of the surfactants. This is why evenexcessive washing with water can not remove the highly solublecyclodextrin component of the polymeric matrices.

The following common water-soluble ionic polymers were involved:

polysaccharides:

Sodium-alginate

Carboxymethyl-cellulose

Carboxymethyl starch

Xanthan gum

Pectin

Tragacantha gum

polyacrylates:

Carbopol 980 NF

Pionier NP 37N

Each of the above three anionic polymers were found to give a positivereaction with quaternary ammonium-type surfactants and cyclodextrins,i.e. they all formed a water insoluble precipitate, as it is describedin detail by the following Examples.

EXAMPLE 5 Preparation ofCarboxymethyl-Cellulose(CMC)/Cetyl-Trimethyl-Ammonium-Bromide(CTAB)/g-Cyclodextrin(gCD) Biomaterial

Two separate aqueous solutions were prepared at room temperature andreacted as follows:

Solution No. 1.: 100 ml of 1% Carboxymethyl-cellulose was prepared andupon stirring at 25° C. 5 g of crystalline gCD was added portionwise anddissolved.

Solution No. 2.: 100 ml of 5% Cetyl-trimethyl-ammonium-bromidecontaining-aqueous solution.

Procedure: Solution No. 2. was added to Solution No. 1. during a slowstirring (around 30 r.p.m.) at 25° C. Upon feeding the solution No. 2. awhite precipitate formed immediately. After the two solutions werethoroughly mixed for 10 minutes with about 30 r.p.m., the formedinsoluble matrix was filtered off on glass filter by vacuum. The wetprecipitate was washed five times with 100 ml of deionised water. Thewater washing was found to improve the consistency, thephysical/mechanical properties (elasticity, hardness) of the matrixformed. The wet washed product was spread in about 3-5 mm thick layerand allowed to dry on air for 12 hours.

Yield: 8.2 % (74%) of white, amorphous polymer was obtained. TABLE 3Composition of polymeric matrices prepared according to Example 4.Analysis of components by HPLC (%)* Sample CMC g-CD CTAB Matrix About 12about 52 about 30 Example 5.

EXAMPLE 5 Preparation of XanthanGum/Cetyl-Trimethyl-Ammonium-Bromide(CTAB)/g-Cyclodextrin (gCD)Biomaterial

Two separate aqueous solutions were prepared at room temperature andreacted as follows:

Solution No. 1.: In 100 ml deionised water 1 g of Xanthan gum wasdissolved, then and upon stirring at 25° C. 5 g of crystalline gCD wasadded. The resulting solution was a slightly turbid, dense, solution.

Solution No. 2.: In 100 ml of deionised water 5 gCetyl-trimethyl-ammonium-bromide was dissolved, resulting in a clear,transparent solution.

Procedure: Solution No. 2. was added to Solution No. 1. during a slowstirring (around 30 r.p.m.) at 25° C. Upon feeding the solution No. 2. acolorless precipitation formed immediately. After the two solutions werethoroughly mixed for 10 minutes with about 30 r.p.m., the formedinsoluble jelly-like matrix was filtered off. The wet slightlyopalescent colorless polymeric body was washed five times with 100 ml ofdeionised water. The wet product was spread In about 3-5 mm thick layersand allowed to dry on air for 12 hours.

Yield: 9.1 g (81%) white, glassy polymer was obtained its composition isshown in Table 4. TABLE 4 HPLC analysis results of the composition ofpolymeric matrices prepared according to Example 6. Analysis results ofcomponents by HPLC (%)* Sample Xanthan gum g-CD CTAB Matrix as per About10 about 50 about 35 Example 6.

EXAMPLE 7 Preparation of Xanthan Gum/BenzalkoniumChlroide(BAC)/g-Cyclodextrin (gCD) Biomaterial

Two separate aqueous solutions were prepared at room temperature andreacted as follows:

Solution No. 1.: In 100 ml deionised water 1 g of Xanthan gum wasdissolved, then and upon stirring at 25° C. 5 g of crystalline gCD wasadded. The resulting solution was a slightly turbid, dense, butstirrable solution.

Solution No. 2.: In 10 ml of 50% (w/v) benzalkonium chloride was used.

Procedure: Solution No. 2. was dropwise added to Solution No. 1. duringa slow stirring (around 45-50 r.p.m.) at 25° C. An immediateprecipitation formation was observed when benzalkonium chloride solutionwas added. After the two solutions were completely unified andthoroughly mixed, dense insoluble colorless polymeric body was formed.The insoluble jelly-like matrix was obtained by filtration. The wetpolymeric body was washed five times with 150 ml of deionised water, andspread into about 3-5 mm thick layers, and allowed to dry on air.

Yield: 10.2 g (92%) colorless polymer was obtained.

EXAMPLE 8 Selection of the Quaternary Ammonium Type SurfactantConstituents for Biomaterial Production

The following commercially available surfactants of different molecularstructure have been selected as suitable ones for making biomaterialsaccording to the present invention:

cetyl-pyridinium-chloride, CPC, (Merck)

cetyl-trimethyl-ammonium-bromide, CTAB, (Merck)

benzalkonium chloride, BAC, (Eu. Pharm. Grade, Novartis)

benzoxonium chloride, BOC, (Eu. Pharm. Grade, Novartis)

cocamidopropyl-N,N,N,trimethyl-glycine (Goldschmidt)

Luviquat™ (BASF) product group of surfactants: Luviquat Hold, LuviquatFC 905, Luviquat FC 550, Luviquat FC 370, Luviquat Care, Luviquat HM552, LuviquatPQ 11 PN, Luviquat MONO CP, LuviquatMONO LS,

EXAMPLE 9 Application of Amino Acid and Amine Derivatives BearingQuaternary Ammonium Moiety for the Preparation of Biomaterial

The substitution of the quaternary ammonium type surfactants withnaturally occurring, more tissue-friendly analogous compounds couldimprove the practical usefulness of these polymeric matrices. Thesystematic screening has lead to the recognition that structurallyanalogous substances carrying a quaternary ammonium moiety withoutlonger alkyl-chain are not appropriate to form a water-insoluble matrixaccording to the present invention. (See Table 5.) TABLE 5 Reaction ofhyaluronic acid, a quaternary ammonium type substance and gCD reactionwith Hyaluronic surfactant substitute acid/gCD remarks choline chlorideno precipitate reaction mixture remains clear L-carnitine no precipitatereaction mixture remains clear N-guanidinomethyl L- no precipitatereaction mixture Arginine remains clear N,N,N,trimethyl-L-Lysine noprecipitate reaction mixture remains clear

It can be seen from the above data, that the presence of a lipophilicpart on the quaternary ammonium-type compounds is an importantprerequisite for precipitate formation, thus the substance must be ofamphiphilic character.

EXAMPLE 10 Selection of the Non-Surfactant Quaternary Ammonium TypeComponents for Building Biomaterials

It has been found that besides the above matrix forming cationicsurfactants some of the naturally occurring, tissue compatiblephospholipids can also be used for making biomaterials according to thepresent invention. However, the hardness and consistency of suchbiomaterials are less favourable than those of the biomaterials made ofsurfactants.

The following substances were found to build polymeric matrices withanionic polymers:

sphyngomyeline

sphyngosine

lysophosphatidyl-choline

EXAMPLE 11 Incorporation of the Water-Soluble Ketotifen HydrogenfumarateDrug Into the Biomaterial According to Example 1

The drug-loaded polymeric matrices can principally be prepared in a onepot reaction. If the drug active to be incorporated is a water solubleone, it will be dissolved together with the cycloldextrin and the watersoluble anionic polymer component. The water insoluble actives can beincorporated in a similar manner, except that they will be dissolvedtogether with the surfactants or phospholipids, as detailed below.

5.0 g of gCD (3.9 mMol) was dissolved in 89.7 g of deionised water. Tothe stirred gCD solution 1.6 g of Ketotifen-hydrogenfumarate (3.9 mMol)was added with continuous stirring. Then 1.0 g of Na-hyaluronate wasadded and the slightly hazy Ketotifen-g-cyclodextrin solution and themixture was stirred with 600 r.p.m. for 60 minutes at 25° C. Thereaction mixture became a dense, viscous solution in about 15 minutes.To this dense solution 3.3 ml of Luviquat Mono CP 30% solution,equvivalent to 1.0 g of surfactant was added dropwise. The clearreaction mixture immediately turned a milky suspension, from which asemi-solid “body”, a precipitate was formed. Further stirring for 30minutes at room temperature a white, rubber-like polymeric matrix wasobtained. The insoluble material was isolated by simple filtration. Thewet product was washed 5-times with 5 ml of cold water, and dried toconstant weight at ambient temperature in vacuum. Yield: 6.2 g (70%yield) of white, glassy solid, with a Ketotifen content of 8.0%.

EXAMPLE 12 Pharmaceutical Performance of the HA/gCD/Mono CP MatrixAccording to Example 1

Two consecutive batches of the polymeric matrix were prepared at labscale and loaded with the selected water-soluble investigational drug,Ketotifen hydrogenfumarate in accordance with the method described inExample 11. The in vitro release profile of the Ketotifen depotformulation was carried out as follows:

1 g of the dry polymeric matrix loaded with Ketotifen-hydrogenfumarateaccording to Example 11. was stirred with 600 r.p.m. in 50 ml ofdeionised water at 37° C. The released amount ofKetotifen-hydrogenfumarate was determined by HPLC. The results of the invitro release test on the two parallel batches are listed in Table 6.TABLE 6 Release of Ketotifen-hydrogenfumarate from two consecutivebatches of the HA/gCD/Luviquat Mono CP polymeric matrix according toExample 1. in deionized water at 37° C. ReleasedKetotifen-hydrogenfumarate (mg/ml) time HA/gCD/Mono CP/drug HA/gCD/MonoCP/drug (minutes) (Batch 1) (Batch 2) 5 0.19 0.20 10 0.29 0.30 20 0.370.42 30 0.45 0.50 40 0.50 0.55 50 0.52 0.56 60 0.50 0.62 80 0.58 0.63100 0.57 0.66 120 0.62 0.64

The above data show that the batch to batch reproducibility of theprocess leading to drug-loaded matrices is acceptable and results inbiomaterials with repoducible pharmaceutical performance. It was foundthat about 40% of that of the total input amount of Ketotifen wasreleased within two hours in stirred aqueous system from the HA/gCD/MonoCP matrix according to Example 1, whilst the release of thenon-formulated plain Ketotifen is a much faster under the sameconditions. (The same system without any stirring, i.e. only allowing tostand in water, will release 40% of the loaded Ketotifen hydrogenfumarate in about 4-5 days only.)

EXAMPLE 13 Effect of the Change of Matrix Composition on the Release ofWater-Soluble Drugs

The change of the composition of the water-insoluble matrices preparedaccording to the present invention was found to affect the releaseprofile of the embedded drugs. Matrices with 8% Ketotifen load wereprepared as described in Example 11. Using two different Hyaluronic acidcontaining reaction mixtures. One contained 1%, while the other 0.5%hyaluronic acid. The reduction of the Hyaluronic acid content in thereaction solution by 50% was found to result in such a drug-loadedbiomaterial, from which the Ketotifen release was much less retarded.(See Table 7.) The in vitro dissolution test was performed as describedin Example 12. TABLE 7 In vitro release of Ketotifen-hydrogenfumarate indeionised water from different HA/gCD/Luviquat Mono CP matrices at 37°C. Released Ketotifen-hydrogenfumarate (mg/ml) time matrix made with1.0% matrix made with 0.5% (minutes) Hyaluronan Hyaluronan 5 0.20 0.4910 0.31 0.60 20 0.37 0.69 30 0.44 0.76 40 0.50 0.78 50 0.55 0.78 60 0.550.79 80 0.60 0.88 100 0.60 0.90 120 0.62 0.95

Based on the above data it can be stated that the in vitro release ofwater soluble drugs from the biodegradable matrices according to thepresent invention can be adjusted by changing the amount of thepolymeric component in the biomaterials.

EXAMPLE 14 Preparation ofCarboxymethyl-Cellulose/Cetyl-Trimethyl-Ammonium-Bromide/g-CyclodextrinBiomaterial

Two separate aqueous solutions were made.

Solution No. b 1.: 100 ml of 1% carboxymethyl-cellulose and 5%

g-cyclodextrin containing aqueous solution

Solution No. 2.: 100 ml of 5% Cetyl-trimethyl-ammonium-bromidecontaining aqueous solution

Procedure:

Solution No. 2. was added to Solution No. 1. during a slow stirring(around 30 r.p.m.) at 25° C. Upon feeding the solution No. 2. animmediate white precipitation occurred. After the two solutions weremixed for 10 minutes with about 30 r.p.m. the formed insoluble matrixwas filtered off by vacuum, and washed 5-times with 100 ml of deionisedwater. The water washing was found to improve the consistency, thephysical/mechanical properties (elasticity, hardness) of the matrixformed. Further washing did not reduce the amount of insoluble material8.1 g white amorphous solid (yield: 74%) was obtained.

EXAMPLE 15 Preparation of Carbopol®980 NF/CetyltrimethylammoniumBromide/Gamma-Cyclodextrin Biomaterial

Solution No. 1.: 5 grams of gCD and 1 gram of the Carbopol® weredissolved in 90 ml of deionised water.

Solution No. 2.: 3.3 ml of 30% Of Luviquat®Mono CP solution.

Procedure: Solution No. 2 was added to the stirred Solution No. 1. at25° C. Upon mixing the two solutions a white precipitate was formed.After about 30 minutes of reaction time no body formation was observed,only a floffy white precipitate was obtained. The reaction mixture wasplaced into refrigerator (5° C.) for 12 hours that resulted in theformation of a dense gel. Dilution of this gel with 4000 ml of deionisedwater, a white insoluble polymeric matrix settled down. The precipitatewas filtered off and washed with 5-times 100 ml of water. The resultingmatrix was 5.3 g white, elastic stable material (yield: 75%).

EXAMPLE 16 Surface Coating With Polymer/Cyclodextrin/SurfactantCombinations

It has been surprisingly found that among the studied anionic polymersCarbopol and carboxymethyl-cellulose provide after reaction withqauternary ammonium type surfactants and cyclodextrin a product that canbe used in diluted form to cover different surfaces with awater-insoluble coating.

Metal, glass and polymer and skin surfaces were treated by applyingafter each other the reaction mixtures according to the presentinvention. (Aqueous polymer and cyclodextrin solutions, followed bycationic surfactant solution). After drying a flexible, but continuouspolymeric layer was formed on the surfaces treated. The coating can notbe washed away not even with excessive amounts of water. Only strongphysical intervention, excessive heat or the bio-erosion will remove ordestroy these coatings. A stainless steel surface was coated withCarbopol/Cetyl-trimethyl-ammonium-bromide/g-cylodextrin composition madeaccording to Example 15. The coating formed on the steel was found toresist to excessive water washings, 20-times 100 ml water washing didnot remove the coating from the surface. However, after 10 times washingwith 100 ml of 0.9% aqueous NaCl solution the physical erosion of thesecoatings was initiated. The extent of physical degradation was found toincrease with increasing ionic strength of the surrounding solutions.

EXAMPLE 17 Surface Coating With Hydrocortison-LoadedPolymer/Cyclodextrin/Surfactant Combinations

Stainless steel surface (area<<15 cm²) was treated after each other withthe following two solutions made according to the present invention:

Solution No. 1.: 5 g of g-cyclodextrin and 1 gram of Carbopol weredissolved in 90 ml of deionised water.

Solution No. 2.: 3.3 ml of 30% Of Luviquat Mono CP solution, containingabout 1 g of cetyl-dimethyl-(2-hydroxyethyl)-ammonium hydrogenphosphate.In this solution 0.19 of hydrocortison was dissolved.

The metal surface was treated by solution No. 1. first followed bysolution No.2 The white precipitate covered the steel surface within 5minutes. The surface was allowed to dry on air. The in vitro release ofthe entrapped hydrocortison from the meatal surface was tested in waterand in 0.9% NaCl solution at 37° C. After 2 hours of stirring in wateronly about 20 μg hydrocortison was released, while during the same timein 0.9% NaCl solution about 90 μg steroid was released.

EXAMPLE 18 Characteristics of the Physical Erosion of thePolymer/Surfactant/Cyclodextrin Matrices

Since the principle of the formation of polymer/cyclodextrin/surfactantinsoluble matrices is the combined effect of the electrostatic andapolar-apolar interactions it was expected that—in accordance withpublished data—the presence of salts (NaCl, Na Br, KCl etc.) willinitiate and accelerate the disassembly of these supramolecularmatrices. Indeed, it was found that in the presence of salts like NaClthese matrices, especially those made of Hyaluronic acid decomposephysically, in a cation concentration dependent manner.

Under isosmotic conditions i.e. in 0.9% NaCl solution the hyaluronicacid/surfactant/gCD insoluble materials turn water-soluble between 8-10days of storage at room temperature.

Under hyperosmotic conditions (e.g. in 5 or 10% NaCl) solution acomplete dissolution of the matrices takes place within 2 days.

The biomaterials made of Carbopol orCarboxymethyl-cellulose/surfactant/cyclodextrin, however, remainphysically much more stable even in 5% NaCl solutions. Thesebiomaterials do not show disintegration after 20 days of storage in 0.9%NaCl. Therefore for longer lasting depot formulation the Carbopol- andCarboxymethyl-cellulose based biomaterials can be preferably used.

EXAMPLE 19 Release of Curcumine From Colorant-Loaded BiomaterialsAccording to the Present Invention

The colorant loaded biomaterials were made by dissolving curcuminecolorant in the surfactant applied. The colorant loaded biomaterialsmade according to Example 11 contained 4.5% curcumine by weight. Theyellow colored matrices were cut into two equal size parts and immersedinto deionised water and to 0.9% NaCl solution. The in vitro releaseprofiles of the colorant from the solid materices was determined asfollows:

10 g of the polymeric matrices loaded with curcumine according toExample 11. were stirred with 600 r.p.m. in 50 ml of deionised water at37° C. The amount of curcumine released was determined byspectrophotometry. The results of the in vitro release test are listedin Table 8. TABLE 8 Release of curcumine from Hyaluronicacid/benzalkonium-chloride/gCD biomaterial in water and in 0.9% NaCl at25° C. Released Curcumine (%)* time (minutes) in water in 0.9% NaCl 51.5 8.5 10 2.9 13.3 20 3.2 13.4 30 3.2 15.3 40 3.5 18.0 50 4.1 18.6 604.5 26.7 80 4.8 27.3 100 5.5 27.6 120 6.2 28.5*If the entire amount of curcumine is released it means 100%

The above data indicate that the extent of release of entrappedmaterials from the biodegradable matrices according to the presentinvention is governed by the actual ionic strength of thedissolution/surrounding media. When such biomaterials loaded withpharmaceutical actives are implanted the release of the entrappedactives will be governed primarily by the ion concentration of thesurrounding tissue, and to a lesser extent by the enzymes present.

EXAMPLE 20 Release of a Steroid Drug From Drug-Loaded BiomaterialsAccording to the Present Invention

The steroid-loaded biomaterial was prepared by dissolving testosteronein the benzalkonium-chloride surfactant. The drug-loaded biomaterialmade according to Example 11 contained 9.0% testosterone by weight. Thetestosterone loaded matrices were cut into two equal size parts andimmersed into deionised water and to 0.9% NaCl solution. The in vitrorelease profiles of the steroid from the solid matrices was determinedas written below:

10 g of the polymeric matrices loaded with testosterone according toExample 11. were stirred with 300 r.p.m. in 100 ml of deionised waterand in 100 ml of 0.9%, 3.0% and 5.0% NaCl solutions at 37° C. The amountof testosterone released was determined by spectrophotometry. Theresults of the in vitro release test are listed in Table 9. TABLE 9 Invitro release profile of testosterone from Hyaluronic acid/benzalkonium-chloride/gCD biomaterial in water and in NaCl solutions of differentconcentrations at 37° C. released testosterone (%) of the total inputamount time hours in water in 0.9% NaCl in 3% NaCl in 5% NaCl 1.5 2.09.8 17.0 18.0 3.0 4.6 12.0 18.0 19.0 6.0 5.5 17.6 18.0 21.2

The above data indicate that the extent of release of entrappedmaterials from the biodegradable matrices according to the presentinvention is regulated by the actual ionic strength of the dissolutionmedia. When this polymer/surfactant/cyclodextrin based biomaterialloaded with testosterone is applied into biological systems, the releaseof the entrapped steroid is initiated by the cation concentration of thesurrounding tissue. This disassembly of the supramolecular matrix by thecations present will be followed by the release of entrappedtestosterone from the gCD complexed form, ensuring a sustained releaseof the testosterone.

EXAMPLE 21 In Situ Formation of Insoluble Biomaterials Loaded withProstaglandin E₂ by two Consecutive Injections

5 of g-cyclodextrin and 1 g of hyaluronic acid are dissolved in 100 mlof sterile deionised water for injection. 2 ml of this dense solution isfilled into an injection syringe.

Another solution is made by dissolving 1 mg Prostaglandin E₂ in 10 ml30% Luviquat Mono CP surfactant. 0.5 ml of this prostaglandin solutionis transferred into an injection syringe. After consecutive subcutaneousinjections to rats the biomaterial loaded with drug is formed in situ.,and a sustained release of prostaglandin is thus ensured.

Any type of compositions described in Examples 1.-15. can be applied asconsecutive injections resulting in the in situ formation of insolublematrices suitable for biomedical and other uses.

EXAMPLE 22 Preparation of a HyaluronicAcid/Surfactant/Phospholipids/Gamma-Cyclodextrin Polymeric Matrix

100 ml volume solution was prepared by dissolving 5 g ofgamma-cyclodextrin and 1 g of hyaluronic acid in deionized water. Thesolution appears a slightly turbid viscous liquid with no solidparticles.

5 ml of 5% aqueous benzalkonium-chloride solution was stirred with 0.3 gof egg yolk-phosphatidylcholine at 40° C., to get a homogeneousemulsion. 10 grams of the above hyaluronic acidly-cyclodextrin solutionwas reacted with 5 ml of phosphatidylcholine/benzalkonium-chlorideemulsion at room temperature. After about 10 minutes of stirring aslightly yellow water insoluble polymeric material was obtained. Thepolymer was filtered off, washed with 5 ml of deionised water and driedin vacuum over P₂O₅ to constant weight.

Yield: 0.62 g (54%) of gummy solid.

The composition of the polymeric material according to Example 22contained about 20% of Hyaluronic acid, 40% of γ-cyclodextrin, 25% ofphospholipid and 8% of benzalkonium chloride.

EXAMPLE 23 Preparation of an Alginic Acid/SurfactantPhospholipids/Gamma-Cyclodextrin Polymeric Matrix

5 ml of 5% aqueous benzalkonium-chloride solution was stirred with 0.3 gof egg yolk-phosphatidylcholine at 40° C., to get a homogeneousemulsion. 10 grams of 1% alginic acid and 5% of gamma-cyclodextrincontaining solution was mixed with 5 ml of phosphatidylcholine/benzalkonium-chloride emulsion at room temperature. After about15 minutes of intense mixing a slightly yellow polymeric precipitate wasformed. The precipitate was filtered off and washed with 5 ml of water.After drying to constant weight 0.55 g of solid elastic gum wasobtained.

EXAMPLE 24 A Surgical Wound Cover Sheet Made of Polymeric MatrixAccording to the Present Invention

Polymeric biomaterial was prepared according to Example 1. The wetproduct was isolated by filtration and washed 3-times with 500 ml ofdeionised water. The washed wet product was rolled on wet glass surfaceinto an about 1 mm thick layer and immersed into cold (about 5° C.)acetone. After about 30 minutes soaking in acetone the product became adehydrated white solid paper-like sheet. After this drying process theacetone was removed by subsequent drying in vacuum. The product can bere-wetted in sterile water whereas it becomes again a visco-elasticpolymer, and can be applied as a wound covering sheet to acceleratewound healing process.

EXAMPLE 25 Antibiotic Wound Dressing/Covering Film Composed fromPolymeric Matrix According to the Present Invention

An antibiotic containing mucoadhesive film was prepared by reacting 100ml of 1% hyaluronic acid solution containing 5 g gamma-cyclodextrin with50 ml of 30% Luviquat Mono CP solution containing 1 g of dissolvedCiprofloxacine. After mixing the two above solutions a white precipitateformed which was removed by filtration. The white polymeric matrix waswashed with 50 ml of water and rolled into a 1 mm thick layer. The wetlayer was dried in vacuum to constant weight. Yield: 10 g of whiteelastic polymer sheet, which contains 7.8% of Cipropfloxacine. Aftersterilization the re-wetting of this polymeric sheet in sterile waterwas found to give a viscoelastic wet film useful for covering of burnedskin surfaces or wounds.

EXAMPLE 26 Conductive Polymeric Matrix Containing Entrapped Iodine

An electric conductive polymeric fiber was prepared by reacting 100 mlof 1% hyaluronic acid solution containing 1 g gamma-cyclodextrin with 50ml of 30% Luviquat Mono CP solution containing 1 g of dissolvedelemental iodine. After mixing the two above solutions a yellowish brownprecipitate formed which was separated by filtration. The polymericmatrix was washed with 50 ml of water and stretched into fibers of about1 or 2 mm diameter. The wet fibers were dried by immersing them intocold (10° C.) acetone and then were vacuum dried. Yield: brown elasticpolymer fibers sheet, which contain about 8% of elemental iodine byweight. The polymeric fiber was found to be electric conductive. Theconductivity was found different in different directions the axialconductivity in direction of stretching was much higher than that of thetransversal. The highly ordered structure of this supramolecularassembly enabled electric conductance even in the polymeric matriceswithout any iodine.

EXAMPLE 27 Allantoin Containing Wound Healing Cover Sheet Composed FromPolymeric Matrix According to the Present Invention

An allantoin containing mucoadhesive film was prepared by reacting 100ml aqueous solution containing 1 g hyaluronic acid and 5 gα-cyclodextrin with 25 ml of 30% Luviquat Mono CP solution containing 2g of dissolved Allantoin. After reacting the two above solutions a whiteprecipitate formed. The polymeric precipitate was removed by filtrationand washed with 25 ml of water. The wet product was rolled into a 1 mmthick homogeneous layer. The wet layer was dried in vacuum to constantweight. Yield: 7.7 g of white polymer sheet. After sterilization there-wetting of this polymeric sheet in sterile water gave a viscoelasticfilm useful for wound dressing to assist healing process.

EXAMPLE 28 A Surgical Thread Composed From Polymeric Matrix According tothe Present Invention

Hyaluronic acid and gamma-cyclodextrin containing solution was reactedaccording to the reaction scheme described in Example 1. with LuviquatMono CP solution containing 2% glycerine. After the reaction wascompleted, the resulting wet polymeric matrix was washed with deionisedwater and then a thread was made by stretching and rolling wet polymerinto a thread of about 0.2 mm thickness. The thread was immediatelysoaked in acetone to dehydrate, and obtain dry, elastic threads.

The resulting threads can be used to surgical closures of wounds. Thesebiodegradable threads can also be employed as implants after they areloaded with appropriate pharmaceutical actives.

EXAMPLE 29 In vitro Enzymatic Degradation of Polymeric Matrices PreparedAccording to the Present Invention

The degradation of hyaluronic acid incorporated into the polymericmatrices according to the present invention was tested at pH 6.5phosphate buffer solution by hyaluronidase enzyme after a 42-hourincubation time, using control, untrapped hyaluronic acid substrate forcomparison. The reaction mixture after stopping enzyme activity wasevaluated by capillary zone electrophoresis. The electropherograms showthat hyaluronic acid is indeed released from the polymeric matrix andgets degraded by the hyaluronidase enzyme. The hyaluronic acid/LuviquatMono CP/gamma-cyclodextrin matrix according to Example 1. was found tobe degradable with the enzyme, but with a slower reaction rate. Thedistribution of the degradation products was similar to those of thecontrol hyaluronic acid, digested by hyaluronidase enzyme.

EXAMPLE 30 The Fate of Implanted Polymeric Matrix According to thePresent Invention in Rats

Two animal studies have been performed. In the first, orientingexperiments three male Whistar rats (average 400 g body weight each)weretreated with very high doses (1 g 2 g and 4 g) of the polymeric matrixaccording to Example 1.

The site of implants on animals were re-opened after two and threeweeks, respectively. The surrounding tissue of the implanted polymericmaterials was visually and microscopically evaluated. Both in case of 1g and 4 g implants the tissue around the implants was found inflamed,moreover, a significant increase in the leukocyte number indicated theinflammation status of treated animals. However, the inflammation foundwas slight, none of the treated animals showed systemic toxicity, eachsurvived well, despite the extremely high applied doses. Three monthsafter implantation the rats receiving 2 g implant were still in perfectcondition.

The HPLC analysis of the tissue/washing liquid samples withdrawn fromthe implant site after 2 weeks, showed that no traces of the hyaluronicacid nor the gamma-cyclodextrin and surfactant could be detected. Thisindirectly proves that the polymeric matrix according to Example 1. iscompletely eliminated after subcutaneous implantation within weeks, evenwhen administered at high dose (4 g per 400 g rat!) thus it seems to bebiodegradable.

EXAMPLE 31 Preparation of a Binary Biomaterial According to theInvention Comprising Carbopol®9880 NF as Anionic Polymer and Luviquat®Mono CP as Surfactant

25 g of gamma-cyclodextrin (gCD) and 5 g of Carbopol®9880 NF aredissolved in 470 g of deionized water at room temperature (25° C.),resulting in a slightly turbid solution. To this solution 17 ml ofLuviquat®Mono CP solution containing 30% (5.1 g) ofcetyl-dimethyl-(2-hydroxy-ethyl)-ammonium dihydrogen-phosphate are addedduring slow stirring. Immediately a white precipitate is formed whichforms an elastic rubber-like body within further 15 minutes. Theisolated wet polymeric body was washed three times with 100 ml ofde-ionized water and dried.

Yield: 9.8 g of a white glassy polymeric material.

Composition of precipitate prepared according to Example 31. Composition(%) Carbopol ® 9880NF gamma-CD Luviquat ® Mono CP about 50 0 about 46

This type of polymeric matrix has an undetectable amount of gamma-CDcontent and is found to be a rather rigid semisolid with no viscoelasticproperties.

The DSC curve of the material registered in N₂ atmosphere shows threesteps of endothermic heat flow together with mass losses. The masslosses are 17.7% in the range up to 250° C., and 25.6% up to 300° C.

EXAMPLE 32 Preparation of a Binary Biomaterial According to theInvention Comprising Carbopol®9880 NF as Anionic Polymer andBenzalkonium Chloride as Surfactant

Solution No. 1: 5 g of gamma-CD and 1 g of Carbopol®9880 NF aredissolved in 94 g of de-ionized water resulting in a slightly turbidsolution.

Solution No. 2: 8 ml of 50% bw. of benzalkonium chloride solution (BAC).

Procedure: Solution No. 2 is added to the stirred solution No. 1 at 25°C. Upon mixing the two solutions a white precipitate is formed. Duringabout 30 minutes of reaction time of reaction time no body is formed andonly a fluffy white precipitate is obtained. The reaction mixture isthen placed into a refrigerator (5° C.) for 12 hours and a dense gel isformed. After dilution of this gel with 4000 ml de-ionized water a whiteinsoluble polymeric material settles down. The precipitate is filteredof and washed five times with 200 ml water. 5.1 g of a white, elastic,rubber-like material are obtained. The mechanical properties of thismaterial are completely different from those of an analogously preparedmaterial based on hyaluronic acid. The polymeric body shows highelasticity and resistance against external forces. It maintains itsshape against any physical intervention due to its considerableresilient properties. The material comprises no gamma-cyclodextrin asshown in the following table.

Composition of precipitate prepared according to Example 32. Composition(%) Carbopol ® 9880NF gamma-CD BAC about 50 0 about 46

EXAMPLE 33 Preparation of a Binary Biomaterial According to theInvention Comprising Pionier®NP 37N Sodium Carbomer as Anionic Polymerand Luviquat® Mono CP as Surfactant

25 g of gamma-cyclodextrin (gCD) and 2.5 g of Pionier®NP 37N SodiumCarbomer are dissolved in 470 g of deionized water at room temperature(25° C.), resulting in a slightly turbid solution. To this solution 9 mlof Luviquat®Mono CP solution containing 30% (2.7 g) ofcetyl-dimethyl-(2-hydroxy-ethyl)-ammonium-dihydrogen-phosphate are addedduring slow stirring. Immediately a white precipitate is formed whichforms an elastic rubber-like body within further 15 minutes. Theisolated wet polymeric body was washed three times with 80 ml ofde-ionized water and dried.

Yield: 3.3 g of a white glassy polymeric material.

Composition of precipitate prepared according to Example 33. Composition(%) Carbopol ® 9880NF gamma-CD Luviquat ® Mono CP about 50 0 about 50

EXAMPLE 34 Tolerability of a Palmitoyl-L-Carnitine/HyaluronicAcid/Gamma-CD Polymeric Matrix in Mice After Subcutaneous Implantation

The Palmitoyl-L-carnitine/Hyaluronic acid/gamma-CD polymeric matrix isprepared under sterile conditions and comprises 53%palmitoyl-L-carnitine, 40% hyaluronic acid, and 2% gamma cyclodextrin.

The test animals are NMRI female mice of an average body weight of 25grams. The animals receive 40 mg of this matrix on the dorsal side ofneck as an implant by a minor surgical intervention. There are also twotypes of “positive control” groups: one group of animals is exposed to“pseudo-surgery” receiving no implants, and the other group receives 40mg of poly-L-lactic acid polymeric implants. After placing and fixingimplants, the general status and leucocyte counts of the test animalsare continuously recorded. In different time intervals the sites of theimplant are re-opened and are checked for an eventual local irritationand/or inflammation caused by the implants. In addition, thebiodegradation of polymeric matrix is evaluated by visual inspection andby light microscopy, and the surrounding tissue of the test animalsaround implants is histologically evaluated.

Results: The results of total leucocyte number of treated and controlanimals as a function of time after receiving implants are summarized inthe next table. Leukocyte counts in control and treated mice afterreceiving 40 mg poly-L-lactic acid and palmitoyl-L-carnitine/Hyaluronicacid/ gamma-CD implants. Total leukocyte count (×10⁶) Day 1 Day 2 Day 4Day 8 Day 21 Control 6.3 4.6 6.2 4.5 6.4 Pseudo- 8.1 5.5 6.6 4.6 3.9surgery PLA* 7.4 5.7 6.2 3.8 4.4 PLC/HA/gCD** 6.2 4.4 6.5 3.9 3.2*poly-L-lactic acid control implant**Palmitoyl-L-carnitine/Hyaluronic acid/gamma-Cyclodextrin matrix

The above data indicate that there is substantially no detectableinflammation caused by the polymeric matrix according to the presentinvention. A significant difference is neither found between the controland treated animals in terms of leucocyte counts after surgicalintervention.

After re-opening the sites of implant, no observable local irritation orinflammation is visually found. Tissue samples taken from the immediatevicinity of implants do no show histological signs of inflammation afterhistochemical/microscopic evaluation. These observations with bloodanalytical data indicate that a subcutaneous implant of thePalmitoyl-L-carnitine/Hyaluronic acid/gamma-CD based polymeric matrix of1.6 g/body weight kg (for human it is ca. 110 g/person) does not causeirritation or any toxicity problems during the observation period of 21days. Moreover, it is found that in mice the average elimination time(time until the Implants physically disappear) of the implantedpolymeric matrix is between three weeks and one month.

1. A precipitate, comprising at least an anionic polymeric componentwhich is as such soluble in water and an amphiphilic ammonium-typecomponent, which precipitate is obtainable by a process including thefollowing steps:
 1. contacting the anionic polymeric component and acyclodextrin component in an aqueous medium, and
 2. adding to themixture obtained in step 1 said amphiphilic ammonium-type component,wherein said components are present in amounts effective to form saidprecipitate.
 2. A precipitate according to claim 1 additionallycomprising said cyclodextrin component.
 3. A precipitate according toclaim 1 additionally comprising one or more further components otherthan said cyclodextrin component which is added in course of step 1and/or 2 of said process.
 4. A precipitate according to claim 3 whereinsaid one or more further components is selected from pharmaceuticallyactive agents, pesticides, agrochemicals, colorants, diagnostics,enzymes and foodstuffs.
 5. A precipitate according to claim 1, whereinthe anionic polymeric component is a member of the group consisting ofhyaluronic acid, carboxymethyl cellulose, carboxymethyl starch, alginicacid, polyacrylic-acid-type polymeric components, pectin, xanthan gum,tragacantha gum, a water soluble salt of one of said components and amixture of two or more of said members.
 6. A precipitate according toclaim 1, wherein said amphiphilic ammonium-type component comprises acationic surfactant.
 7. A precipitate according to claim 1, wherein saidamphiphilic ammonium-type component is selected from the groupconsisting of benzalkonium-chloride, benzoxonium-chloride,cetyl-pyridinium chloride, cetyltrimethylammonium bromide,cetyldimethyl(2-hydroxyethyl)ammonium dihydrogen phosphate (Luviquat®Mono CP), cocamidopropyl-N,N,N,trimethyl-glycine, acyl carnitines,sodium cocyl glutamate and mixtures of one or more members of saidgroup.
 8. A precipitate according to claim 1, wherein said amphiphilicammonium-type component comprises a cationic phospholipid.
 9. Aprecipitate according to claim 8, wherein the cationic phospholipid isselected from lysophosphatidyl-choline compounds, phosphatidyl cholinecompounds, sphingomyelin, sphingosine derivatives and mixtures thereof.10. A precipitate according to claim 1, wherein the cyclodextrincomponent is selected from alpha-cyclodextrin, beta-cyclodextrin,gamma-cyclodextrin and mixtures thereof.
 11. A precipitate according toclaim 4, wherein the one or more further components comprise apharmaceutically active agent.
 12. A precipitate according to claim 11,wherein the pharmaceutically active agent is selected from the groupconsisting of steroids, prostanoids, nitric-oxide prodrugs,antihistamines, antibiotics, cytostatic agents, antivirals, peptidehormones, local anesthetics, antiglaucoma agents, antiinflammatoryagents, antihypertensives, antiangiogenic agents and suitablecombinations thereof.
 13. A process for manufacturing a precipitateaccording to claim 1, wherein the anionic polymeric component, thecyclodextrin component and further components comprised in saidprecipitate which are soluble in water are dissolved in an aqueousmedium to form a first composition; the amphiphilic component andfurther components comprised in said precipitate which are insoluble inwater are blended with a suitable liquid carrier, to form a secondcomposition, and said first and second composition are blended to formsaid precipitate.
 14. A process according to claim 13, wherein theprecipitate is brought into a desired shape.
 15. A process according toclaim 13 including a treatment of a non-liquid carrier for coating itwith said first composition and a subsequent treatment of the so-treatedcarrier with said second composition for forming a coating of saidprecipitate on said carrier.
 16. A pharmaceutical composition comprisinga precipitate according to claim
 11. 17. A pharmaceutical compositionaccording to claim 16, which is a depot formulation.
 18. A medicaldevice comprising a precipitate according to claim
 11. 19. A medicalimplant or insert according to claim
 18. 20. A kit for administering apharmaceutical composition according to claim 16, to a subject bysimultaneous or consecutive administration of parts of said compositionto said subject thereby forming the composition in situ at the place ofadministration, which kit comprises two or more than two partialcompositions, each comprising one or more of the components of saidpharmaceutical composition, whereby the components intended to form theprecipitate are present in said compositions for consecutive orsimultaneous administration in amounts effective to form theprecipitate.
 21. A kit according to claim 20 comprising a firstcomposition comprising the anionic polymeric component, the cyclodextrincomponent and the further components comprised in said precipitate whichare soluble in water, dissolved in an aqueous medium; and a secondcomposition comprising the amphiphilic component and componentscomprised in said precipitate which are insoluble in water, blended witha suitable liquid carrier, preferably an aqueous medium.
 22. A kitaccording to claim 20 adjusted to a subcutaneous or intramuscularadministration of the pharmaceutical composition.
 23. A kit according toclaim 20 adjusted to the administration of the pharmaceuticalcomposition onto wounds, skin or other solid surfaces by spraying.
 24. Amethod of administering a pharmaceutically active compound to a subjectin need thereof, comprising the administration of a pharmaceuticalcomposition according to claim 16 comprising said pharmaceuticallyactive compound.
 25. A method for administering a pharmaceuticalcomposition according to claim 16 to a subject including thesimultaneous or consecutive administration of two or more than twopartial compositions, each comprising one or more of the components ofsaid pharmaceutical composition, thereby forming the pharmaceuticalcomposition in situ at the place of administration, wherein thecomponents intended to form the precipitate are present in said partialcompositions in amounts effective to form the precipitate when contactedwith one another.
 26. A method according to claim 25 including thesimultaneous consecutive administration of a first compositioncomprising the anionic polymeric component, the cyclodextrin componentand the further components comprised in said precipitate which aresoluble in water, dissolved in an aqueous medium; and a secondcomposition comprising the amphiphilic component and componentscomprised in said precipitate which are insoluble in water, blended witha suitable liquid carrier, preferably an aqueous medium.
 27. A methodaccording to claim 25 wherein the partial compositions aresubcutaneously or intramuscularly injected in the subject.
 28. A methodaccording to claim 25 wherein the partial compositions are administeredonto wounds, skin or other solid surfaces, preferably by spraying.